U.S. patent application number 15/160593 was filed with the patent office on 2016-09-15 for dry powder formulation comprising an anticholinergic, a corticosteroid and a beta-adrenergic for administration by inhalation.
This patent application is currently assigned to CHIESI FARMACEUTICI S.p.A.. The applicant listed for this patent is CHIESI FARMACEUTICI S.p.A.. Invention is credited to Azita Askey-Sarvar, Rossella Musa, Irene PASQUALI, Francesca Schiaretti.
Application Number | 20160263027 15/160593 |
Document ID | / |
Family ID | 51292914 |
Filed Date | 2016-09-15 |
United States Patent
Application |
20160263027 |
Kind Code |
A1 |
PASQUALI; Irene ; et
al. |
September 15, 2016 |
DRY POWDER FORMULATION COMPRISING AN ANTICHOLINERGIC, A
CORTICOSTEROID AND A BETA-ADRENERGIC FOR ADMINISTRATION BY
INHALATION
Abstract
Dry powder formulations for inhalation comprising a combination
of an anticholinergic, a long-acting beta.sub.2-adrenoceptor
agonist, and a corticosteroid are useful for the prevention and/or
treatment of inflammatory and/or obstructive airways diseases.
Inventors: |
PASQUALI; Irene; (Parma,
IT) ; Musa; Rossella; (Parma, IT) ;
Schiaretti; Francesca; (Parma, IT) ; Askey-Sarvar;
Azita; (Parma, IT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
CHIESI FARMACEUTICI S.p.A. |
Parma |
|
IT |
|
|
Assignee: |
CHIESI FARMACEUTICI S.p.A.
Parma
IT
|
Family ID: |
51292914 |
Appl. No.: |
15/160593 |
Filed: |
May 20, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
14327920 |
Jul 10, 2014 |
9402825 |
|
|
15160593 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 45/06 20130101;
A61K 9/145 20130101; A61J 3/02 20130101; A61P 11/06 20180101; A61P
11/00 20180101; A61K 31/167 20130101; A61M 15/00 20130101; A61K
31/573 20130101; Y10S 514/958 20130101; A61P 11/08 20180101; A61K
31/40 20130101; A61K 9/0075 20130101; A61K 31/167 20130101; A61K
2300/00 20130101; A61K 31/40 20130101; A61K 2300/00 20130101; A61K
31/573 20130101; A61K 2300/00 20130101 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61K 31/167 20060101 A61K031/167; A61J 3/02 20060101
A61J003/02; A61K 31/40 20060101 A61K031/40; A61M 15/00 20060101
A61M015/00; A61K 9/14 20060101 A61K009/14; A61K 31/573 20060101
A61K031/573 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 11, 2013 |
EP |
13176114.0 |
Nov 28, 2013 |
EP |
13194763.2 |
Claims
1. A dry powder formulation for use in a dry powder inhaler (DPI),
comprising: (a) a fraction of fine particles, consisting of a
mixture, prepared by co-mixing in a high-energy apparatus for a
period of less than 20 minutes, of 90 to 99.5 percent by weight of
micronized particles of a physiologically acceptable excipient and
0.5 to 10 percent by weight of magnesium stearate, wherein at least
90% of all said particles have a volume diameter lower than 15
microns and the volume median diameter of said particles is from 3
to 7 microns; (b) a fraction of coarse particles consisting of a
physiologically acceptable excipient having a mass median diameter
equal to or higher than 100 microns, wherein the ratio between said
fine particles (a) and said coarse particles (b) is from 1:99 to
30:70 percent by weight; and (c) micronized particles of an
anticholinergic, an inhaled corticosteroid (ICS), and a long-acting
.beta..sub.2-agonist (LABA) as active ingredients.
2. A dry powder formulation according to claim 1, wherein at least
90% of all said fine particles have a volume diameter lower than 12
microns, and the volume median diameter of said fine particles is
from 4 to 6 microns.
3. A powder formulation according to claim 1, wherein no more than
10% of said fine particles (a) have a diameter lower than 1.8
microns.
4. A powder formulation according to claim 1, wherein no more than
10% of said fine particles (a) have a diameter lower than 1.5
microns.
5. A powder formulation according to claim 1, wherein said LABA is
formoterol fumarate dihydrate, said ICS is beclometasone
dipropionate, and said anticholinergic is glycopyrronium
bromide.
6. A powder formulation according to claim 1, wherein said high
energy apparatus is a mechano-fusion apparatus.
7. A powder formulation according to claim 1, wherein said high
energy apparatus is the CYCLOMIX.TM. apparatus.
8. A power formulation according claim 1, wherein said magnesium
stearate coats the surface of said particles of excipient particles
(a) in such a way that the extent of the surface coating is at
least of 50%.
9. A dry powder formulation for use in a dry powder inhaler (DPI),
comprising: (a) a fraction of fine particles consisting of a
mixture of 90 to 99.5 percent by weight of particles of a
physiologically acceptable excipient and 0.5 to 10 percent by
weight of magnesium stearate, wherein at least 90% of all said
particles have a volume diameter lower than 15 microns, and the
volume median diameter of said particles is from 3 to 7 microns;
(b) a fraction of coarse particles consisting of a physiologically
acceptable excipient having a mass median diameter equal to or
higher than 100 microns, wherein the ratio between said fine
particles (a) and said coarse particles (b) is from 1:99 to 30:70
percent by weight; and (c) micronized particles of an
anticholinergic, an inhaled corticosteroid (ICS), and a long-acting
.beta..sub.2-agonist (LABA) as active ingredients, wherein at least
90% of all said micronized particles of said active ingredients
have a volume diameter lower than 6.0 microns, and the volume
median diameter of said particles is from 1.2 to 2.5 microns.
10. A dry powder formulation according to claim 9, wherein at least
90% of all said fine particles (a) have a volume diameter lower
than 12 microns, and the volume median diameter of said particles
is from 4 to 6 microns; and wherein at least 90% of all said
micronized particles of said active ingredients (c) have a volume
diameter equal to or lower than 5.0 microns, and the volume median
diameter of said particles is from 1.3 to 2.2 microns.
11. A powder formulation according to claim 7, wherein said LABA is
formoterol fumarate dihydrate, said ICS is beclometasone
dipropionate and said anticholinergic is glycopyrronium
bromide.
12. A dry powder formulation for use in a dry powder inhaler (DPI),
comprising: (a) a fraction of fine particles consisting of a
mixture of 90 to 99.5 percent by weight of particles of
alpha-lactose monohydrate and 0.5 to 10 percent by weight of
magnesium stearate, wherein at least 90% of said particles have a
volume diameter lower than 12 microns and the volume median
diameter of said particles is from 4 to 6 microns; (b) a fraction
of coarse particles consisting of alpha-lactose monohydrate having
a mass median diameter equal to or higher than 175 microns, wherein
the ratio between the fine particles and the coarse particles being
between 5:95 and 15:85 percent by weight; and (c) micronized
particles of formoterol fumarate dihydrate, glycopyrronium bromide,
and optionally beclometasone dipropionate as active ingredients,
wherein at least 90% of all said micronized particles of the active
ingredients have a volume diameter lower than 6.0 microns, and the
volume median diameter of said particles is from 1.2 to 2.5
microns.
13. A dry powder formulation according to claim 12, wherein at
least 90% of all said micronized particles of the active
ingredients (c) have a volume diameter equal to or lower than 5.0
microns, and the volume median diameter of said particles is from
1.3 to 2.2 microns.
14. A process for preparing a dry powder formulation according to
claim 1, comprising mixing said fraction of fine particles (a),
said fraction of coarse lactose particles (b) and all the
micronized active ingredients.
15. A process for preparing a dry powder formulation according to
claim 9, comprising mixing said fraction of fine particles (a),
said fraction of coarse lactose particles (b) and all the
micronized active ingredients.
16. A dry powder inhaler device, containing a dry powder
formulation according to claim 1.
17. A dry powder inhaler device, containing a dry powder
formulation according to claim 9.
18. A dry powder inhaler device, containing a dry powder
formulation according to claim 12.
19. A method for the prevention and/or treatment of an inflammatory
and/or obstructive airways disease, comprising administering an
effective amount of a formulation according to claim 1 to a subject
in need thereof.
20. A method according to claim 19, wherein said inflammatory
and/or obstructive airways disease is chronic obstructive pulmonary
disease (COPD).
21. A method for the prevention and/or treatment of an inflammatory
and/or obstructive airways disease, comprising administering an
effective amount of a formulation according to claim 9 to a subject
in need thereof.
22. A method according to claim 21, wherein said inflammatory
and/or obstructive airways disease is chronic obstructive pulmonary
disease (COPD).
23. A method for the prevention and/or treatment of an inflammatory
and/or obstructive airways disease, comprising administering an
effective amount of a formulation according to claim 12 to a
subject in need thereof.
24. A method according to claim 23, wherein said inflammatory
and/or obstructive airways disease is chronic obstructive pulmonary
disease (COPD).
Description
CROSS REFERENCES TO RELATED APPLICATIONS
[0001] This application claims priority to European Patent
Application No. 13176114.0, filed on Jul. 11, 2013 and European
Patent Application No. 13194763.2, filed on Nov. 28, 2013, both of
which are incorporated herein by reference in their entireties.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to formulations for
administration by inhalation by means of dry powder inhalers. In
particular, the present invention relates to dry powder
formulations comprising a combination of an anticholinergic, a
beta.sub.2-adrenoceptor agonist, and an inhaled corticosteroid,
process for their preparation and use thereof for the prevention
and/or treatment of respiratory diseases.
[0004] 2. Discussion of the Background
[0005] Respiratory diseases are a common and important cause of
illness and death around the world. In fact, many people are
affected by inflammatory and/or obstructive lung diseases, a
category characterized by inflamed and easily collapsible airways,
obstruction to airflow, problems exhaling and frequent medical
clinic visits and hospitalizations. Types of inflammatory and/or
obstructive lung disease include asthma, bronchiectasis, bronchitis
and chronic obstructive pulmonary disease (COPD).
[0006] In particular, chronic obstructive pulmonary disease (COPD)
is a multi-component disease characterized by airflow limitation
and airway inflammation. Exacerbations of COPD have a considerable
impact on the quality of life, daily activities and general
well-being of patients and are a great burden on the health system.
Thus, the aims of COPD management include not only relieving
symptoms and preventing disease progression but also preventing and
treating exacerbations.
[0007] While available therapies improve clinical symptoms and
decrease airway inflammation, they do not unequivocally slow
long-term progression or address all disease components. With the
burden of COPD continuing to increase, research into new and
improved treatment strategies to optimize pharmacotherapy is
ongoing, and in particular, combination therapies, with a view to
their complementary modes of action enabling multiple components of
the disease to be addressed. Evidence from recent clinical trials
indicates that triple therapy, combining an anticholinergic with an
inhaled corticosteroid, and a long-acting 13.sub.2-adrenoceptor
agonist, may provide clinical benefits additional to those
associated with each treatment alone in patients with more severe
COPD.
[0008] Currently, there are several recommended classes of therapy
for COPD, of which bronchodilators such as .beta..sub.2-agonists
and anticholinergics are the mainstay of symptom management in mild
and moderate disease, prescribed on an as-needed basis for mild
COPD and as a maintenance therapy for moderate COPD.
[0009] Said bronchodilators are efficiently administered by
inhalation, thus increasing the therapeutic index and reducing side
effects of the active material.
[0010] For the treatment of more severe COPD, guidelines recommend
the addition of inhaled corticosteroids (ICSs) to long-acting
bronchodilator therapy. Combinations of therapies have been
investigated with a view to their complementary modes of action
enabling multiple components of the disease to be addressed. Data
from recent clinical trials indicate that triple therapy, combining
an anticholinergic with an ICS and a long-acting
.beta..sub.2-agonist (LABA), may provide clinical benefits
additional to those associated with each treatment alone in
patients with moderate to severe COPD.
[0011] An interesting triple combination, presently under
investigation, includes: [0012] i) formoterol, particularly its
fumarate salt (hereinafter indicated as FF), a long acting beta-2
adrenergic receptor agonist, currently used clinically in the
treatment of bronchial asthma, COPD and related disorders; [0013]
ii) glycopyrronium bromide, an anticholinergic recently approved
for the maintenance treatment of COPD; [0014] iii) beclometasone
dipropionate (BDP) a potent anti-inflammatory corticosteroid
steroid, available under a wide number of brands for the
prophylaxis and/or treatment of asthma and other respiratory
disorders.
[0015] Formulations for pressurized metered dose inhalers (pMDIs)
containing all said three active ingredients in combination are
disclosed in WO 2011/076841 and WO 2011/076843, which are
incorporated herein by reference in their entireties.
[0016] However, despite their popularity, pMDI formulations may
have some disadvantages in particular in elderly patients, mostly
due to their difficulty to synchronize actuation from the device
with inspiration.
[0017] Dry powder inhalers (DPIs) are a valid alternative to MDIs
for the administration of drugs to airways and lung. Active
ingredients intended for inhalation as dry powders should be used
in the form of micronized particles.
[0018] In order to manufacture a single suitable DPI product
containing said kinds of active ingredients, the dry powder
formulation should have acceptable flowability to facilitate both
handling and the aerosol performance of all three actives from the
device.
[0019] This is challenging task, as it is well known that by
increasing the numbers and the concentration of the active
ingredients, the higher is the risk of forming uneven agglomerates
which are detrimental to the possibility of achieving a good
uniformity of distribution of the active ingredient in the powder
mixture and hence a good accuracy of the dose. Said phenomenon has
also a detrimental effect on the flowability of the relevant
formulation, which in turn would impact on the capability of the
device of delivering the correct dose due to the active particles
being unable to leave the inhaler and remaining adhered to its
interior.
[0020] Therefore, the presence of three active ingredients with
different physical and chemical properties to be delivered at three
different dosage strengths within the same device creates serious
problems in the preparation of homogenous blends as well as in the
delivery of them with suitable respirable fractions.
[0021] WO 01/78693, which is incorporated herein by reference in
its entirety, discloses a technology platform for preparing a dry
powder formulation comprising as a carrier, a combination of a
fraction of coarse excipient particles and a fine fraction made of
fine excipient particles and magnesium stearate.
[0022] The formulation therein disclosed is described as freely
flowable, physically and chemically stable and capable of
delivering both accurate doses and a high fraction of fine active
particles (respirable fraction).
[0023] However, there are no examples reported demonstrating that
said platform would be suitable for a combination of three
different active ingredients.
[0024] Furthermore, good results in terms of respirable fraction
are only obtained if the fine fraction of the carrier is prepared
starting from coarse excipient particles and the additive, and
subjecting them to co-milling for long times, at least two hours,
or to jet-milling.
[0025] Therefore it would be highly advantageous to provide a
powder formulation for administration with DPIs comprising a
combination of an anticholinergic, an inhaled corticosteroid, and a
long-acting .beta..sub.2-agonist as active ingredients, overcoming
all the aforementioned disadvantages.
SUMMARY OF THE INVENTION
[0026] Accordingly, it is one object of the present invention to
provide novel powder formulations for administration with a DPI
comprising a combination of an anticholinergic, an inhaled
corticosteroid, and a long-acting I.beta..sub.2-agonist as active
ingredients.
[0027] It is another object of the present invention to provide
novel DPIs which contain such a formulation.
[0028] It is another object of the present invention to provide
novel methods of preparing such a formulation.
[0029] It is another object of the present invention to provide
novel methods of preventing/treating certain diseases and/or
conditions by administering an effective amount of such a
composition.
[0030] These and other objects, which will become apparent during
the following detailed description, have been achieved by the
inventors' discovery of dry powder formulations for use in a dry
powder inhaler (DPI) comprising:
[0031] a) a fraction of fine particles, prepared by co-mixing in a
high-energy apparatus for a period of less than 20 minutes,
consisting of a mixture of 90 to
99.5 percent by weight of micronized particles of a physiologically
acceptable excipient and 0.5 to 10 percent by weight of magnesium
stearate, wherein at least 90% of all said particles have a volume
diameter lower than 15 micron, preferably lower than 12 micron, and
the volume median diameter of said particles is comprised between 3
and 7 micron, preferably between 4 and 6 micron;
[0032] b) a fraction of coarse particles consisting of a
physiologically acceptable excipient having a mass median diameter
equal to or higher than 100 micron, wherein the ratio between the
fine particles and the coarse particles being between 1:99 and
30:70 percent by weight; and
[0033] c) micronized particles of an anticholinergic, an inhaled
corticosteroid (ICS), and a long-acting .beta..sub.2-agonist (LABA)
as active ingredients.
[0034] Preferably, the LABA is formoterol fumarate dihydrate, the
ICS is beclometasone dipropionate and the anticholinergic is
glycopyrronium bromide.
[0035] In a second aspect, the present invention provides dry
powder formulations for use in a dry powder inhaler (DPI)
comprising:
[0036] a) a fraction of fine particles consisting of a mixture of
90 to 99.5 percent by weight of particles of a physiologically
acceptable excipient and 0.5 to 10 percent by weight of magnesium
stearate, wherein at least 90% of all said particles have a volume
diameter lower than 15 micron, preferably lower than 12 micron, and
the volume median diameter of said particles is comprised between 3
and 7 micron, preferably between 4 and 6 micron;
[0037] b) a fraction of coarse particles consisting of a
physiologically acceptable excipient having a mass median diameter
equal to or higher than 100 micron, wherein the ratio between the
fine particles and the coarse particles being between 1:99 and
30:70 percent by weight; and
[0038] c) micronized particles of an anticholinergic, an inhaled
corticosteroid (ICS), and a long-acting .beta..sub.2-agonist (LABA)
as active ingredients,
[0039] wherein the at least 90% of all said micronized particles of
the active ingredients have a volume diameter equal to or lower
than 6.0 micron, preferably equal to or lower than 5.0 micron, and
the volume median diameter of said particles is comprised between
1.2 and 2.5 micron, preferably between 1.3 and 2.2 micron.
[0040] Preferably, the LABA is formoterol fumarate dihydrate, the
ICS is beclometasone dipropionate and the anticholinergic is
glycopyrronium bromide.
[0041] In a third aspect, the present invention provies dry powder
formulations for use in a dry powder inhaler (DPI) comprising:
[0042] a) a fraction of fine particles consisting of a mixture of
90 to 99.5 percent by weight of particles of alpha-lactose
monohydrate and 0.5 to 10 percent by weight of magnesium stearate,
wherein at least 90% of said particles have a volume diameter lower
than 12 micron, and the volume median diameter of said particles is
comprised between 4 and 6 micron;
[0043] b) a fraction of coarse particles consisting of
alpha-lactose monohydrate having a mass median diameter equal to or
higher than 175 micron, wherein the ratio between the fine
particles and the coarse particles being between 5:95 and 15:85
percent by weight; and
[0044] c) micronized particles of formoterol fumarate dihydrate,
glycopyrronium bromide, and optionally beclometasone dipropionate
as active ingredients,
[0045] wherein the at least 90% of all said micronized particles of
the active ingredients have a volume diameter lower than 6.0
micron, preferably equal to or lower than 5.0 micron, and the
volume median diameter of said particles is comprised between 1.2
and 2.5 micron, preferably between 1.3 and 2.2 micron.
[0046] In a fourth aspect, the present invention provides processes
for preparing the aforementioned dry powder formulations.
[0047] In a fifth aspect, the present invention provides dry powder
inhaler devices filled with the above dry powder formulations.
[0048] In a sixth aspect, the present invention provides such
formulations for use in the prevention and/or treatment of an
inflammatory and/or obstructive airways disease, in particular
chronic obstructive pulmonary disease (COPD).
[0049] In a seventh aspect, the present invention provides methods
of preventing and/or treating an inflammatory and/or obstructive
airways disease, in particular chronic obstructive pulmonary
disease (COPD), which comprises administering by inhalation of an
effective amount of such a formulation.
[0050] In an eighth aspect, the present invention provides the use
of such formulations in the manufacture of a medicament for the
prevention and/or treatment of an inflammatory and/or obstructive
airways disease in particular chronic obstructive pulmonary disease
(COPD).
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0051] The terms "muscarinic receptor antagonists," "antimuscarinic
drugs," and "anticholinergic drugs" can be used synonymously.
[0052] The term "pharmaceutically acceptable salt of
glycopyrrolate" refers to a salt of the compound (3S,2'R),
(3R,2'S)-3-[(cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidiniu-
m in approximately 1:1 racemic mixture, also known as
glycopyrronium salt.
[0053] The term "pharmaceutically acceptable salt of formoterol"
refers to a salt of the compound 2'-hydroxy-5'-[(RS)-1-hydroxy-2
{[(RS)-p-methoxy-.alpha.-methylphenethyl]amino}ethyl]formanilide.
[0054] The term "beclometasone dipropionate" refers to the compound
(8S,9R,10S,11S,13S,14S,16S,17R)-9-chloro-11-hydroxy-10,13,16-trimethyl-3--
oxo-17-[2-(propionyloxy)acetyl]-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydr-
o-3H-cyclopenta[a]phenanthren-17-yl propionate.
[0055] The term "pharmaceutically acceptable salt" comprises
inorganic and organic salts. Examples of organic salts may include
formate, acetate, trifluoroacetate, propionate, butyrate, lactate,
citrate, tartrate, malate, maleate, succinate, methanesulfonate,
benzenesulfonate, xinafoate, pamoate, and benzoate. Examples of
inorganic salts may include fluoride chloride, bromide, iodide,
phosphate, nitrate and sulphate.
[0056] The expression "high energy apparatus" refers to an
apparatus that generates high compression and shear forces
(mechanical energy) achieved by repeated compression of the powder
bed in the centrifugal field.
[0057] The term "micronized" refers to a substance having a size of
few microns.
[0058] The term "coarse" refers to a substance having a size of one
or few hundred microns.
[0059] In general terms, the particle size of particles is
quantified by measuring a characteristic equivalent sphere
diameter, known as volume diameter, by laser diffraction. The
particle size can also be quantified by measuring the mass diameter
by means of suitable known instrument such as, for instance, the
sieve analyzer.
[0060] The volume diameter (VD) is related to the mass diameter
(MD) by the density of the particles (assuming a size independent
density for the particles).
[0061] In the present application, the particle size of the active
ingredients and of fraction of fine particles is expressed in terms
of volume diameter, while that of the coarse particles is expressed
in terms of mass diameter.
[0062] The particles have a normal (Gaussian) distribution which is
defined in terms of the volume or mass median diameter (VMD or MMD)
which corresponds to the volume or mass diameter of 50 percent by
weight of the particles, and, optionally, in terms of volume or
mass diameter of 10% and 90% of the particles, respectively.
[0063] Another common approach to define the particle size
distribution is to cite three values: i) the median diameter d(0.5)
which is the diameter where 50% of the distribution is above and
50% is below; ii) d(0.9), where 90% of the distribution is below
this value; iii) d(0.1), where 10% of the distribution is below
this value.
[0064] The span is the width of the distribution based on the 10%,
50% and 90% quantile and is calculated according to the
formula.
Span = D [ v , 0.9 ] - D [ v , 0.1 ] D [ v , 0.5 ] ##EQU00001##
[0065] In general terms, particles having the same or a similar
VIVID or MMD can have a different particle size distribution, and
in particular a different width of the Gaussian distribution as
represented by the d(0.1) and d(0.9) values.
[0066] Upon aerosolization, the particle size is expressed as mass
aerodynamic diameter (MAD), while the particle size distribution is
expressed in terms of mass median aerodynamic diameter (MMAD) and
Geometric Standard Deviation (GSD). The MAD indicates the
capability of the particles of being transported suspended in an
air stream. The MMAD corresponds to the mass aerodynamic diameter
of 50 percent by weight of the particles.
[0067] In the final formulation, the particle size of the active
ingredients can be determined by scanning electron microscopy
according to methods known to the skilled person in the art.
[0068] The term "hard pellets" refers to spherical or semispherical
units whose core is made of coarse excipient particles.
[0069] The term "spheronization" refers to the process of rounding
off of the particles which occurs during the treatment.
[0070] The term "good flowability" refers to a formulation that is
easy handled during the manufacturing process and is able to ensure
an accurate and reproducible delivery of the therapeutically
effective dose.
[0071] Flow characteristics can be evaluated by different tests
such as angle of repose, Carr's index, Hausner ratio or flow rate
through an orifice.
[0072] In the context of the present invention, the flow properties
were tested by measuring the flow rate through an orifice according
to the method described in the European Pharmacopeia (Eur. Ph.)
7.3, 7th Edition, which is incorporated herein by reference in its
entirety.
[0073] The expression "good homogeneity" refers to a powder
wherein, upon mixing, the uniformity of distribution of a
component, expressed as coefficient of variation (CV) also known as
relative standard deviation (RSD), is less than 5.0%. It is usually
determined according to known methods, for instance by taking
samples from different parts of the powder and testing the
component by HPLC or other equivalent analytical methods.
[0074] The expression "respirable fraction" refers to an index of
the percentage of active particles which would reach the lungs in a
patient.
[0075] The respirable fraction is evaluated using a suitable in
vitro apparatus such as Andersen Cascade Impactor (ACI), Multi
Stage Liquid Impinger (MLSI) or Next Generation Impactor (NGI),
according to procedures reported in common Pharmacopoeias, in
particular in the European Pharmacopeia (Eur. Ph.) 7.3, 7th
Edition, which is incorporated herein by reference in its
entirety.
[0076] It is calculated by the percentage ratio of the fine
particle mass (formerly fine particle dose) to the delivered
dose.
[0077] The delivered dose is calculated from the cumulative
deposition in the apparatus, while the fine particle mass is
calculated from the deposition of particles having a diameter
<5.0 microns.
[0078] In the context of the present invention, the formulation is
defined as an extrafine formulation when it is capable of
delivering a fraction of particles having a particle size equal or
less than 2.0 microns equal to or higher than 20%, preferably equal
to or higher than 25%, more preferably equal to or higher than 30%
and/or it is capable of delivering a fraction of particles having a
particle size equal or less than 1.0 micron equal to or higher than
10%.
[0079] The expression "physically stable in the device before use"
refers to a formulation wherein the active particles do not
substantially segregate and/or detach from the surface of the
carrier particles both during manufacturing of the dry powder and
in the delivery device before use. The tendency to segregate can be
evaluated according to Staniforth et al. J. Pharm. Pharmacol.
34,700-706, 1982, which is incorporated herein by reference in its
entirety, and it is considered acceptable if the distribution of
the active ingredient in the powder formulation after the test,
expressed as relative standard deviation (RSD), does not change
significantly with respect to that of the formulation before the
test.
[0080] The expression "chemically stable" refers to a formulation
that, upon storage, meets the requirements of the EMEA Guideline
CPMP/QWP/122/02 referring to `Stability Testing of Existing Active
Substances and Related Finished Products,` which is incorporated
herein by reference in its entirety.
[0081] The term "surface coating" refers to the covering of the
surface of the carrier particles by forming a film of magnesium
stearate around said particles. The thickness of the film has been
estimated by X-ray photoelectron spectroscopy (XPS) to be
approximately of less than 10 nm. The percentage of surface coating
indicates the extent by which magnesium stearate coats the surface
of all the carrier particles.
[0082] The term "prevention" means an approach for reducing the
risk of onset of a disease.
[0083] The term "treatment" means an approach for obtaining
beneficial or desired results, including clinical results.
Beneficial or desired clinical results can include, but are not
limited to, alleviation or amelioration of one or more symptoms or
conditions, diminishment of extent of disease, stabilized (i.e. not
worsening) state of disease, preventing spread of disease, delay or
slowing of disease progression, amelioration or palliation of the
disease state, and remission (whether partial or total), whether
detectable or undetectable. The term can also mean prolonging
survival as compared to expected survival if not receiving
treatment.
[0084] According to the Global Initiative for Asthma (GINA), which
is incorporated herein by reference in its entirety, "severe
persistent asthma" is defined as a form characterized by daily
symptoms, frequent exacerbations, frequent nocturnal asthma
symptoms, limitation of physical activities, forced expiratory
volume in one second (FEV.sub.1) equal to or less than 60%
predicted and with a variability higher than 30%.
[0085] According to the Global initiative for chronic Obstructive
Pulmonary Disease (GOLD) guidelines, which is incorporated herein
by reference in its entirety, "severe COPD" is a form characterized
by a ratio between FEV.sub.1 and the Forced Vital Capacity (FVC)
lower than 0.7 and FEV.sub.1 between 30% and 50% predicted. The
very severe form is further characterized by chronic respiratory
failure.
[0086] "Therapeutically effective dose" means the quantity of
active ingredients administered at one time by inhalation upon
actuation of the inhaler. Said dose may be delivered in one or more
actuations, preferably one actuation (shot) of the inhaler.
"Actuation" refers to the release of active ingredients from the
device by a single activation (e.g. mechanical or breath).
[0087] The present invention is directed to dry powder formulations
for use in a dry powder inhaler (DPI) comprising a fraction of fine
excipients particles a), a fraction of coarse excipient particles
b), and micronized particles of an anticholinergic, an inhaled
corticosteroid (ICS), and a long-acting .beta..sub.2-agonist (LABA)
as active ingredients.
[0088] The LABA active ingredients, that may be present in form of
pharmaceutically acceptable salts and/or solvate form thereof, can
be selected from the group, which includes, but it is not limited
to, formoterol, salmeterol, indacaterol, and vilanterol.
[0089] The anticholinergics, that are usually present in form of
pharmaceutically acceptable inorganic salts, can be selected from
the group which includes, but it is not limited to, glycopyrronium
bromide or chloride, tiotropium bromide, and aclidinium
bromide.
[0090] The ICS, that may be anhydrous or present in form of
hydrates, can be selected from the group which includes, but it is
not limited to, beclomethasone dipropionate and its monohydrate
form, budesonide, fluticasone propionate, fluticasone furoate, and
mometasone furoate.
[0091] Preferably, the LABA is formoterol fumarate dihydrate, the
ICS is beclometasone dipropionate, and the anticholinergic is
glycopyrronium bromide.
[0092] The fractions a) and b) are the "carrier" particles.
[0093] The fraction of fine particles a) is prepared by co-mixing
in a high-energy apparatus for a period of less than 30
minutes.
[0094] Said fraction consists of 90 to 99.5 percent by weight of
micronized particles of a physiologically acceptable excipient and
0.5 to 10 percent by weight of magnesium stearate (optionally
micronized), wherein at least 90% of said particles have a volume
diameter lower than 15 micron, preferably lower than 12 micron, and
the volume median diameter of said particles is comprised between 3
and 7 micron, preferably between 4 and 6 micron.
[0095] Since the co-mixing step does not alter the particle size of
the fraction of said particles, the person skilled in the art shall
select the suitable size of the fine particles of the
physiologically acceptable excipient as well as of magnesium
stearate to achieve the desired particle size distribution in terms
of both volume diameter of 90% of the particles and volume median
diameter (50%).
[0096] Materials of the desired particle size distribution are
commercially available.
[0097] In a preferred embodiment of the present invention, no more
than 10% of said particles have a diameter lower than 1.8 micron,
preferably lower than 1.5 micron.
[0098] The last feature is considered particular advantageous as a
fraction of fine particles a) containing a higher amount of finer
particles might create problems of flowability of the whole powder
formulation.
[0099] It has been found that the technology platform disclosed in
WO 01/78693, which is incorporated herein by reference in its
entirety, might be suitable for preparing a dry powder formulation
comprising three different active ingredients at different
therapeutically effective dosages.
[0100] However, the inventors found that the fraction of fine
particles constituting part of the carrier can be obtained in a
much shorter time by subjecting the micronized excipient of the
desired particle size and magnesium stearate (optionally
micronized) to co-mixing in particular apparatus rather than
co-milling coarse particles of the excipient with magnesium
stearate.
[0101] Besides reducing the time of processing, this also improves
the versatility of the formulation, as in this way it would be
possible to target the final particle size of the fine fraction a)
by pre-selecting it, as the co-mixing step does not affect the size
of the particles, while by co-milling it isn't so easy to control
the particle size of the final fine blend.
[0102] In comparison to what reported in WO 01/78693, which is
incorporated herein by reference in its entirety, it has also
surprisingly been found that, by carrying out the co-mixing step in
particular apparatus, it is possible to provide formulations
capable of delivering respirable fractions for each active
ingredient higher than 50%.
[0103] The formulation according to the present invention also
shows a good homogeneity of the active ingredients, a good
flowability and adequate physical and chemical stability in the
inhaler before use for pharmaceutical purposes.
[0104] In an embodiment of the invention, the fraction of fine
particles a) may be prepared by co-mixing in a mechano-fusion
apparatus.
[0105] Mechano-fusion is a simple, dry mechanical process that is
designed to apply thin layers of lubricants to the particle
surfaces without impacting on the original size of the
particles.
[0106] The fine excipient particles and the magnesium stearate
particles are fed into the mechano-Fusion driven vessel, where they
are subject to a centrifugal force and are pressed against the
vessel inner wall. The powder is compressed between the fixed
clearance of the drum wall and a curved inner element with high
relative speed between drum and element. The inner wall and the
curved element together form a gap or nip in which the particles
are pressed together. As a result the particles experience very
high shear forces and very strong compressive stresses as they are
trapped between the inner drum wall and the inner element (which
has a greater curvature than the inner drum wall).
[0107] The particles violently collide against each other with
enough energy to locally heat and soften, break, distort, flatten
and wrap the particles of hydrophobic material around the core
particle to form a coating. The energy is generally sufficient to
break up agglomerates, while the particle size of the excipient
particles remains substantially the same and a high extent of
coating with magnesium stearate is achieved.
[0108] Either the outer vessel or the inner element may rotate to
provide the relative movement. The gap between these surfaces is
relatively small, and is typically less than 10 mm and is
preferably less than 5 mm, more preferably less than 3 mm. This gap
is fixed, and consequently leads to a better control of the
compressive energy than is provided in some other forms of mill
such as ball mills. Also, preferably, no impaction of milling media
surfaces is present so that wear and consequently contamination are
minimized.
[0109] A scraper may also be present to break up any caked material
building up on the vessel surface. The local temperature may be
controlled by use of a heating/cooling jacked built into the drum
vessel walls. The powder may be re-circulated through the
vessel.
[0110] Apparatus such as Nobilta.TM. and Nanocular.TM.
mechano-fusion processors from Hosokawa Micron Corporation, Japan,
are preferably utilized. Both systems comprise a cylindrical vessel
with a rotating axial shaft (rotor). In the Nobilta.TM. processor,
the paddles extend along the length of the axial shaft, and extend
out to within approximately 1 mm of the vessel wall. Consequently,
as the shaft rotates, the blades continuously sweep close to the
vessel wall, ensuring all the powder is in constant and violent
motion. Due to the high rotational speed of the paddles, the powder
is propelled towards the wall, and as a result the mixture
experiences very high shear forces at the paddle face, and
compressive stresses between wall and paddle.
[0111] In the Nanocular.TM. processor, the motion is similar, but
with less impact due to absence of the paddle faces, and a higher
degree of compressive stresses between wall and press head.
[0112] The time of the process will depend on the specific
processor, and it shall be suitably adjusted by the skilled person
depending on the size of the batch. However, the process shall be
carried out for a time no longer than 20 minutes, advantageously
for a time comprised between 2 and 15 minutes, more advantageously
for 10 minutes.
[0113] The product temperature remained constant during all the
experiments. However, the temperature may be controlled in an
accurate and reliable way by means of a cooling jacket system
typically set a 15-25.degree. C.
[0114] The speed of rotation shall depend on the specific
mechano-fusion processor, type of rotor and related number of
paddles, as well as on the size of the processed batch, and shall
be suitably adjusted by the skilled person in the art.
[0115] Typically, a speed of rotation not higher than 5000 rpm may
be utilized, advantageously comprised between 500 and 4000 rpm.
[0116] In an embodiment of the present invention, the particles are
processed at 500 rpm for ten minutes.
[0117] In an alternative embodiment of the present invention, the
fraction of fine particles a) may be prepared by co-mixing in a
high energy mixer based on friction, operating at a rotation speed
comprised between 100 rpm and 2500 rpm, preferably between 500 and
2000 rpm, more preferably between 1000 and 1500 rpm.
[0118] A typical high energy mixer which could be employed for
carrying out the process of the invention is the CYCLOMIX.TM.
apparatus (Hosokawa Micron Group Ltd). Said apparatus comprises a
stationary conical vessel fitted with paddle-shaped mixing
elements, which rotate close to the inner vessel wall.
[0119] The powder loaded into the conical mixing vessel from the
top; the degree of filling can range between 30 and 100%. Together,
the rotation of the paddles and the conical shape of the vessel
force the powder from the bottom to the upper zone of the vessel.
Upon reaching the top, the powder flows downwards into the center
of the vessel. This flow pattern results in fast mixing. During the
upward motion, the particles of the powder are accelerated by the
paddles and intensively mixed by friction with vessel. Such effects
are sufficient to soften, break, distort, flatten and wrap the
particles of magnesium stearate around the carrier particles to
form a coating.
[0120] The product temperature remained constant during all the
experiments. However, the temperature may be controlled in an
accurate and reliable way by means of a cooling jacket system
typically set a 15-25.degree. C.
[0121] When the process is carried within the claimed limits in
terms of rotating speed, the particle size of the excipient
particles remain substantially the same and a high extent of
coating with magnesium stearate is achieved.
[0122] The time of the process may be suitably adjusted by the
skilled person in the art depending on the size of the batch.
[0123] However, the process shall be carried out for a time no
longer than 20 minutes, advantageously for a time comprised between
2 and 15 minutes, preferably for a time equal to or lesser than 10
minutes.
[0124] Advantageously, the fine and coarse excipient particles may
consist of any pharmacologically inert, physiologically acceptable
material or combination thereof; preferred excipients are those
made of crystalline sugars, in particular lactose; the most
preferred are those made of .alpha.-lactose monohydrate.
[0125] Preferably, the coarse excipient particles and the fine
excipient particles both consist of .alpha.-lactose
monohydrate.
[0126] Advantageously, magnesium stearate coats the surface of the
excipient particles of fine fraction a) in such a way that the
extent of the surface coating is at least of 10%, more
advantageously, higher than 20%
[0127] In some embodiments, depending on the amount of magnesium
stearate used as well as on the processing conditions, an extent of
the surface coating higher than 50%, preferably higher than 60%
could be achieved.
[0128] The extent to which the magnesium stearate coats the surface
of the excipient particles may be determined by X-ray photoelectron
spectroscopy (XPS), a well-known tool for determining the extent as
well as the uniformity of distribution of certain elements on the
surface of other substances. In the XPS instrument, photons of a
specific energy are used to excite the electronic states of atoms
below the surface of the sample. Electrons ejected from the surface
are energy filtered via a hemispherical analyser (HSA) before the
intensity for a defined energy is recorded by a detector. Since
core level electrons in solid-state atoms are quantized, the
resulting energy spectra exhibit resonance peaks characteristic of
the electronic structure for atoms at the sample surface.
[0129] Typically XPS measurements are taken on an Axis-Ultra
instrument available from Kratos Analytical (Manchester, UK) using
monochromated Al K.alpha. radiation (1486.6 eV) operated at 15 mA
emission current and 10 kV anode potential (150 W). A low energy
electron flood gun is used to compensate for insulator charging.
Survey scans, from which quantification of the detected elements
are obtained, are acquired with analyser pass energy of 160 eV and
a 1 eV step size. High-resolution scans of the C 1s, O 1s, Mg 2s, N
1s and Cl 2p regions are acquired with pass energy of 40 eV and a
0.1 eV step size. The area examined is approximately 700
.mu.m.times.300 .mu.m for the survey scans and a 110 .mu.m diameter
spot for the high-resolution scans.
[0130] In the context of the present invention, by XPS, it is
possible to calculate both the extent of coating and the depth of
the magnesium sterate film around the lactose particles. The extent
of magnesium stearate (MgSt) coating is estimated using the
following equation:
% MgSt coating=(% Mg.sub.sample/% Mg.sub.ref).times.100
where:
[0131] Mg.sub.sample is the amount of Mg in the analyzed
mixture;
[0132] Mg.sub.ref is the amount of Mg in the reference sample of
commercially available MgSt.
[0133] Usually the values are calculated as a mean of two different
measurements. Typically, an accuracy of 10% is quoted for routinely
performed XPS experiments.
[0134] Alternatively, when the excipient particles are made of
lactose, preferably of alpha-lactose monohydrate, the extent of
surface coating may be determined by water contact angle
measurement, and then by applying the equation known in the
literature as Cassie and Baxter, for example cited at page 338 of
Colombo I et al 11 Farmaco 1984, 39(10), 328-341, which is
incorporated herein by reference in its entirey, and reported
below.
cos .sub.mixture=f.sub.MgSt cos .sub.Mgst+f.sub.lactose cos
.sub.lactose
where:
[0135] f.sub.Mgst and f.sub.lactore are the surface area fractions
of magnesium stearate and of lactose;
[0136] .sub.mgSt is the water contact angle of magnesium
stearate;
[0137] .sub.lactose is the water contact angle of lactose
[0138] .sub.mixture are the experimental contact angle values.
[0139] For the purpose of the present invention, the contact angle
may be determined with methods that are essentially based on a
goniometric measurement. These imply the direct observation of the
angle formed between the solid substrate and the liquid under
testing. It is therefore quite simple to carry out, being the only
limitation related to possible bias stemming from intra-operator
variability. It should be, however, underlined that this drawback
can be overcome by adoption of a fully automated procedure, such as
a computer assisted image analysis. A particularly useful approach
is the sessile or static drop method which is typically carried out
by depositing a liquid drop onto the surface of the powder in form
of disc obtained by compaction (compressed powder disc method).
[0140] Within the limits of the experimental error, a good
consistency has been found between the values of extent of coating
as determined by XPS measurements, and those as estimated by the
theoretical calculations based on the Cassie and Baxter
equation.
[0141] The extent to which the magnesium stearate coats the surface
of the excipient particles may also be determined by scanning
electron microscopy (SEM), a well-known versatile analytical
technique.
[0142] Such microscopy may be equipped with an EDX analyzer (an
Electron Dispersive X-ray analyzer), that can produce an image
selective to certain types of atoms, for example magnesium atoms.
In this manner it is possible to obtain a clear data set on the
distribution of magnesium stearate on the surface of the excipient
particles.
[0143] SEM may alternatively be combined with IR or Raman
spectroscopy for determining the extent of coating, according to
known procedures.
[0144] Optionally, the fraction of fine particles a) may be
subjected to a conditioning step according to the conditions
disclosed in WO 2011/131663, which is incorporated herein by
reference in its entirety.
[0145] The coarse excipient particles of the fraction b) must have
mass median diameter equal to or higher than 100 micron preferably
equal to or greater than 125 micron, more preferably equal to or
greater than 150 micron, even more preferably equal to or greater
than 175 micron.
[0146] Advantageously, all the coarse particles have a mass
diameter in the range 50-1000 micron, preferably comprised between
60 and 500 micron.
[0147] In certain embodiments of the present invention, the mass
diameter of said coarse particles might be comprised between 80 and
200 micron, preferably between 90 and 150 micron, while in another
embodiment, the mass diameter might be comprised between 200 and
400 micron, preferably between 210 and 355 micron.
[0148] In a preferred embodiment of the present invention, the mass
diameter of the coarse particles is comprised between 210 and 355
micron.
[0149] In general, the person skilled in the art shall select the
most appropriate size of the coarse excipient particles by sieving,
using a proper classifier.
[0150] When the mass diameter of the coarse particles is comprised
between 200 and 400 micron, the coarse excipient particles
preferably have a relatively highly fissured surface, that is, on
which there are clefts and valleys and other recessed regions,
referred to herein collectively as fissures. The "relatively highly
fissured" coarse particles can be defined in terms of fissure index
or rugosity coefficient as described in WO 01/78695 and WO
01/78693, both of which are incorporated herein by reference in
their entireties, and they could be characterized according to the
description therein reported. Advantageously, the fissure index of
said coarse particles is of at least 1.25, preferably of at least
1.5, more preferably of at least 2.0, while the rugosity
coefficient is of at least 1.25.
[0151] Said coarse particles may also be characterized in terms of
tapped density or total intrusion volume measured as reported in WO
01/78695, which is incorporated herein by reference in its
entirety.
[0152] The tapped density of said coarse particles could
advantageously be less than 0.8 g/cm.sup.3, preferably between 0.8
and 0.5 g/cm.sup.3. The total intrusion volume could be of at least
0.8 cm.sup.3, preferably at least 0.9 cm.sup.3.
[0153] The ratio between the fraction of fine particles a) and the
fraction of coarse particles b) shall be comprised between 1:99 and
30:70% by weight, preferably between 2:98 and 20:80% by weight.
[0154] In a preferred embodiment, the ratio is comprised between
5:95 and 15:85% by weight.
[0155] In certain embodiments, the ratio is of 10:90 by weight,
while in other embodiments, the ratio might be 5:95 by weight.
[0156] The step of mixing the coarse excipient particles b) with
the fraction of fine particles a) is typically carried out in
suitable mixers, e.g. tumbler mixers such as Turbula.TM. or
Dynamix.TM., rotary mixers, or instant mixer such as Diosna.TM.,
for at least 5 minutes, preferably for at least 30 minutes, more
preferably for at least two hours.
[0157] In a general way, the person skilled in the art shall adjust
the time of mixing and the speed of rotation of the mixer to obtain
a homogenous mixture.
[0158] When spheronized coarse excipient particles are desired to
obtain hard-pellets according to the definition reported above, the
step of mixing shall be typically carried out for at least four
hours.
[0159] Advantageously, each active ingredient is present in the
formulation of the invention in a crystalline form, more preferably
with a crystallinity degree higher than 95%, even more preferably
higher than 98%, as determined according to known methods.
[0160] Since the formulation of the present invention should be
administered to the lungs by inhalation, at least 90% of the
micronized particles of each active ingredient should have a volume
diameter equal to or lower than 6 micron.
[0161] On the other hand, it is well known that most of the
available formulations tend to be associated with a poor
therapeutic control of individuals exhibiting respiratory diseases
affecting the small airways such as the small airways asthma
phenotype.
[0162] Therefore there is need of "extrafine" formulations of
inhaled corticosteroids in combination with long-acting
.beta.-agonists and anticholinergics which could reach the distal
tract of the respiratory tree and hence improving small airways
outcomes and associated control.
[0163] Accordingly, in a particular embodiment of the present
invention, the micronized particles of each active ingredient are
characterized by a selected, narrow, and well defined particle size
distribution capable of reaching said distal tract of the
respiratory tree.
[0164] Therefore, the invention is also directed to a dry powder
formulation for use in a dry powder inhaler (DPI) comprising:
[0165] a) a fraction of fine particles consisting of a mixture of
90 to 99.5 percent by weight of particles of a physiologically
acceptable excipient and 0.5 to 10 percent by weight of magnesium
stearate, wherein at least 90% of all said particles have a volume
diameter lower than 15 micron, preferably lower than 12 micron, and
the volume median diameter of said particles is comprised between 3
and 7 micron, preferably between 4 and 6 micron;
[0166] b) a fraction of coarse particles consisting of a
physiologically acceptable excipient having a mass median diameter
equal to or higher than 100 micron, wherein the ratio between the
fine particles and the coarse particles being between 1:99 and
30:70 percent by weight; and
[0167] c) micronized particles of an anticholinergic, an inhaled
corticosteroid (ICS), and a long-acting .beta..sub.2-agonist (LABA)
as active ingredients, wherein the at least 90% of all said
micronized particles of the active ingredients have a volume
diameter lower than 6.0 micron, preferably equal to or lower than
5.0 micron, and the volume median diameter of said particles is
comprised between 1.2 and 2.5 micron, preferably between 1.3 and
2.2 micron.
[0168] In this case, the fraction of fine particles a) could be
obtained according to any of the methods disclosed in WO 01/78693,
which is incorporated herein by reference in its entirety, for
example by co-milling or by co-mixing as reported on page 15, lines
5-15. In an alternative embodiment, it might be obtained by
co-mixing in a high-energy apparatus according to the conditions
disclosed in the present application.
[0169] Preferably, the LABA is formoterol fumarate dihydrate, the
ICS is beclometasone dipropionate and the anticholinergic is
glycopyrronium bromide.
[0170] Advantageously, no more than 10% of all said micronized
particles of the active ingredients have a diameter lower than 0.6
micron, preferably equal to or lower than 0.7 micron, more
preferably equal to or lower than 0.8 micron.
[0171] It follows that the width of the particle size distribution
of the particles of each active ingredient, expressed as a span,
should be advantageously comprised between 1.0 and 4.5, more
advantageously between 1.2 and 3.0, preferably between 1.3 and 2.1,
more preferably between 1.6 and 2.0. According the Chew et at J
Pharm Pharmaceut Sci 2002, 5, 162-168, which is incorporated herein
by reference in its entirety, the span corresponds to [d (v,
0.9)-d(v,0.1)]/d(v,0.5).
[0172] Even more advantageously, at least 99% of said particles
[d(v,0.99)] shall have a volume diameter equal to or lower than 7.0
micron, and substantially all the particles have a volume diameter
comprised between 6.8 and 0.4 micron, preferably between 6.5 and
0.45 micron.
[0173] The size of the particles active is determined by measuring
the characteristic equivalent sphere diameter, known as volume
diameter, by laser diffraction. In the reported examples, the
volume diameter has been determined using a Malvern apparatus.
However, other equivalent apparatus may be used by the skilled
person in the art.
[0174] In order to provide an extrafine formulation comprising
formoterol fumarate dihydrate, BDP, and glycopyrronium bromide as
active ingredients, it would also be preferable that the micronized
particles of BDP have a Specific Surface Area comprised between 5.5
and 7.0 m.sup.2/g, preferably between 5.9 and 6.8 m.sup.2/g, the
micronized particles of formoterol fumarate dihydrate have a
Specific Surface Area comprised between 5 and 7.5 m.sup.2/g,
preferably between 5.2. and 6.5 m.sup.2/g, more preferably between
5.5 and 5.8 m.sup.2/g, and the micronized particles of
glycopyrronium bromide have a Specific Surface Area comprised
between 3.0 and 6.0 m.sup.2/g, preferably between 3.5 and 4.5
m.sup.2/g.
[0175] The Specific Surface Area is determined by
Brunauer-Emmett-Teller (BET) nitrogen adsorption method according
to a known procedure known.
[0176] All the micronized active ingredients utilized in the
formulation of the invention may be prepared by processing in a
suitable mill according to known methods.
[0177] In one embodiment of the invention, they could be prepared
by grinding using a conventional fluid energy mill such as
commercially available jet mill micronizers having grinding
chambers of different diameters.
[0178] Depending on the type of the apparatus and size of the
batch, the person skilled in the art shall suitably adjust the
milling parameters such as the operating pressure, the feeding rate
and other operating conditions to achieve the desired particle
size. In a particular embodiment, the micronized particles of
glycopyrronium bromide may be prepared according to the process
disclosed in EP 13165483.2, which is incorporated herein by
reference in its entirety.
[0179] In a particularly preferred embodiment, the present
invention is directed dry powder formulation for use in a dry
powder inhaler (DPI) comprising:
[0180] a) a fraction of fine particles consisting of a mixture of
90 to 99.5 percent by weight of particles of alpha-lactose
monohydrate and 0.5 to 10 percent by weight of magnesium stearate,
wherein at least 90% of said particles have a volume diameter lower
than 12 micron, and the volume median diameter of said particles is
comprised between 4 and 6 micron;
[0181] b) a fraction of coarse particles consisting of
alpha-lactose monohydrate having a mass median diameter equal to or
higher than 175 micron, wherein the ratio between the fine
particles and the coarse particles being between 5:95 and 15:85
percent by weight; and
[0182] c) micronized particles of formoterol fumarate dihydrate,
glycopyrronium bromide, and optionally beclometasone dipropionate
as active ingredients,
[0183] wherein the at least 90% of all said micronized particles of
the active ingredients have a volume diameter lower than 6.0
micron, preferably equal to or lower than 5.0 micron, and the
volume median diameter of said particles is comprised between 1.2
and 2.5 micron, preferably between 1.3 and 2.2 micron.
[0184] Advantageously, beclometasone dipropionate is present as
third active ingredient.
[0185] The present invention is also related to processes for
preparing the dry powder formulations disclosed herein comprising
the step of mixing the fraction of fine particles a), the fraction
of coarse lactose particles b) and all the micronized active
ingredients.
[0186] In one embodiment, the carrier particles comprising the
fraction of fine particles a) and the fraction of coarse particles
b) may be prepared by mixing in suitable apparatus known to the
skilled person in the art, for example a Turbula.TM. mixer. The two
fractions are preferably mixed in a Turbula.TM. mixer operating at
a rotation speed of 11 to 45 rpm, preferably 16 to 32 rpm for a
period comprised between 30 and 300 minutes, preferably between 150
and 240 minutes.
[0187] Also the mixing of the carrier particles with the active
ingredient particles may be carried out by mixing the components in
suitable known apparatus, such as a Turbula.TM. or Dynamix.TM.
mixer for a sufficient period to achieve the homogeneity of the
active ingredient in the final mixture. Advantageously, the mixing
is carried out for a time comprised between 30 and 120 minutes,
preferably between 45 and 100 minutes.
[0188] Optionally, in an alternative embodiment, one active
ingredient is first mixed with a portion of the carrier particles
and the resulting blend is forced through a sieve, then, the two
further active ingredients and the remaining part of the carrier
particles are blended with the sieved mixture; finally, the
resulting mixture is sieved through a sieve, and mixed again.
[0189] The skilled person in the art shall select the mesh size of
the sieve depending on the particle size of the coarse
particles.
[0190] In a particular embodiment, when the fraction of fine
particles a) can be prepared according to any of the methods
disclosed in WO 01/78693, which is incorporated herein by reference
in its entirety, the powder formulation of the present invention
might be prepared by co-mixing the micronized particles of the
excipients, the particles of magnesium and the coarse excipients
particles all together in a proper apparatus, followed by the
addition of the micronized active ingredients to the resulting
mixture, and mixing again.
[0191] The ratio between the carrier particles and the active
ingredients will depend on the type of inhaler used and the
required dose.
[0192] The powder formulations of the present invention may be
suitable for delivering a therapeutic amount of all active
ingredients in one or more actuations (shots or puffs) of the
inhaler.
[0193] Advantageously, the formulations of the invention shall be
suitable for delivering a therapeutically effective dose of all
three active ingredients comprised between 50 and 600 .mu.g,
preferably between 100 and 500 .mu.g.
[0194] For example, the formulations will be suitable for
delivering 3-12 .mu.g formoterol (as fumarate dihydrate) per
actuation, especially 6 .mu.g or 12 .mu.g per actuation, 25-200
.mu.g beclometasone dipropionate (BDP) per actuation, especially
50, 100 or 200 .mu.g per actuation, and 10-65 .mu.g glycopyrronium
(as bromide), especially 12.5 .mu.g or 25 .mu.g.
[0195] The dry powder formulation of the invention may be utilized
with any dry powder inhaler.
[0196] Dry powder inhaler (DPIs) can be divided into two basic
types: i) single dose inhalers, for the administration of single
subdivided doses of the active compound; each single dose is
usually filled in a capsule; and ii) multidose inhalers pre-loaded
with quantities of active principles sufficient for longer
treatment cycles.
[0197] The dry powder formulations of the invention are
particularly suitable for multidose DPIs comprising a reservoir
from which individual therapeutic dosages can be withdrawn on
demand through actuation of the device, for example that described
in WO 2004/012801, which is incorporated herein by reference in its
entirety.
[0198] Other multidose devices that may be used are, for instance,
the DISKUS.TM. of GlaxoSmithKline, the TURBOHALER.TM. of
AstraZeneca, the TWISTHALER.TM. of Schering and the CLICKHALER.TM.
of Innovata.
[0199] As marketed examples of single dose devices, there may be
mentioned ROTOHALER.TM. of GlaxoSmithKline, HANDIHALER.TM. of
Boehringer Ingelheim, Breezehaler.TM. of Novartis, and Monodose
RS01 of Plastiape.
[0200] In a preferred embodiment, when an extrafine formulation
according to the invention is utilized, the dry powder formulation
is filled in the DPI device disclosed in WO 2004/012801, which is
incorporated herein by reference in its entirety, being
particularly suitable for the delivery of extrafine
formulation.
[0201] To protect the DPIs from ingress of moisture into the
formulation, it may be desirable to overwrap the device in a
flexible package capable of resisting moisture ingress such as that
disclosed in EP 1760008, which is incorporated herein by reference
in its entirety.
[0202] Administration of the formulations of the present invention
is preferably indicated for the prevention and/or treatment of
chronic obstructive pulmonary disease (COPD). However, said
formulation might also be indicated for the prevention and/or
treatment of asthma of all types and severity, including severe
persistent asthma, as well as further respiratory disorders
characterized by obstruction of the peripheral airways as a result
of inflammation and presence of mucus such as chronic obstructive
bronchiolitis.
[0203] In certain embodiments, the formulations of the present
invention are suitable for the prevention and/or treatment of
severe and/or very severe forms of respiratory disorders, in
particular severe and/or very severe forms of COPD.
[0204] Other features of the invention will become apparent in the
course of the following descriptions of exemplary embodiments which
are given for illustration of the invention and are not intended to
be limiting thereof.
EXAMPLES
Example 1
Preparation of the Fraction of Fine Particles a) by
Mechano-Fusion
[0205] Several batches made of about 25 g micronized alpha-lactose
monohydrate (Meggle, Germany) mixed with different amounts of
magnesium stearate from Peter Greven, Germany (MgSt) were fed into
the 100 ml driven vessel of the mechano-fusion apparatus AMS-MINI
(Hosokawa Micron Corporation) equipped with two different rotors.
The driven vessel was also equipped with a cooling jacket system
set up at 15.degree. C. The process was conducted according to the
conditions reported in Table 1.
TABLE-US-00001 TABLE 1 Rotation Processing speed time MgSt Batch
(rpm) (min) (%) 1C 3000 10 2 1D 4000 10 2 2C 3000 10 2 2D 4000 10 2
GK/A 500 10 0.5 GK/B 500 10 1 GK/C 500 10 2 GK/D 500 10 3
[0206] The obtained mechano-fused microparticles were collected and
subjected to technological characterization.
Example 2
Technological Characterization of the Fine Particles of Example
1
[0207] The fine particles as obtained in Example 1 were subjected
to the following analyses.
Scanning Electron Microscopy (SEM).
[0208] Morphological properties were investigated using a scanning
electron microscope (Phenom.TM., FEI Company, Hillsboro, Oreg.).
Each sample was carefully mounted on a sample holder, so as to
ensure representative images, and sputter coated with gold. SEM
micrographs were taken using in-built image capture software.
Particle Size Distribution.
[0209] Particle size distributions were measured by laser
diffraction (Mastersizer.RTM. S, Malvern Instruments,
Worcestershire, UK). The parameter taken into consideration was the
VD in micron of 10%, 50% and 90% of the particles expressed as
d(v,0.1), d(v, 0.5) and d(v, 0.9), respectively, which correspond
to the mass diameter assuming a size independent density for the
particles. The results are reported in Table 2.
Uniformity of Distribution.
[0210] The uniformity of distribution of MgSt was evaluated by
withdrawing 12 samples from different parts of the powder, then its
content determined by HPLC analysis. The results in terms of
Relative Standard Deviation (RSD) are reported in Table 2 for
batches GK/A, GK/B, GK/C, and GK/D.
MgSt Coating.
[0211] The extent to which the magnesium stearate coats the surface
of the lactose particles was determined by X-ray photoelectron
spectroscopy (XPS) using an Axis-Ultra instrument available from
Kratos Analytical (Manchester, UK) and according to the conditions
reported in the specification.
TABLE-US-00002 TABLE 2 MgSt MgSt uniformity Particle size (.mu.m)
coating Batch RSD d (v0.1) d (v0.5) d (v0.9) (%) GK/A 2.97 1.17
4.58 10.62 10.6 GK/B 2.26 1.15 4.55 10.60 17.7 GK/C 3.99 1.19 4.68
10.80 20.9 GK/D 2.84 1.18 4.70 10.96 21.5
[0212] Both SEM and Malvern analysis indicate that the particle
size distribution of the fine particles do not substantially change
in comparison to the particle size of the starting particles of
alpha-lactose monohydrate. Moreover, MgSt shows a good homogeneity
inside the blend.
[0213] Batches 1C, 1D, 2C and 2D showed an extent of MgSt coating
ranging from 60 to 65%, indicating that a higher speed of rotation
could contribute to improvement of the extent of coating.
Example 3
Preparation of the Fraction of Fine Particles a) Using the Cyclomix
Apparatus
[0214] About 25 g of alpha-lactose monohydrate mixed with 2% w/w of
magnesium stearate were fed into the stationary conical vessel of a
5 liter laboratory model CYCLOMIX.TM. apparatus (Hosokawa Micron
Ltd) and processed at 125 rpm for 20 minutes (batch C23) or at 500
rpm for 10 minutes (batch C24). The obtained particles were
collected and subjected to the chemico-physical technological
characterization reported in the Example 2.
[0215] Batch C23 showed an extent of MgSt coating of 14.9%, while
batch C24 showed an extent of MgSt coating of 19.9%.
Example 4
Preparation of the "Carrier" [Fraction a)+Fraction b)]
[0216] Samples of the batch GK/C (Example 1) and C23 (Example 3)
were separately mixed with fissured coarse particles of
.alpha.-lactose monohydrate having a mass diameter comprised
between 212-355 micron, and obtained by sieving, in the ratio 90:10
percent by weight. The mixing was carried out in a Turbula mixer
operating at a rotation speed of 32 rpm for a period of 240
minutes. The resulting mixtures of particles are termed hereinafter
as carriers MF (deriving from mechano-fusion) and CY (deriving from
Cyclomix).
Example 5
Preparation of the Dry Powder Formulations
[0217] A portion of each carrier as obtained in Example 4 was mixed
with micronized formoterol fumarate dihydrate (FF) in a Turbula
mixer for 30 minutes at 32 r.p.m. and the resulting blend was
forced through a sieve with mesh size of 0.3 mm (300 micron).
Micronized beclometasone dipropionate (BDP) and glycopyrronium
bromide (GB) and the remaining part of the carrier were blended in
a Turbula mixer for 120 minutes at 32 r.p.m. with the sieved
mixture to obtain the final formulations MF and CY. Each final
formulation was passed through a sieve with mesh size of 0.4 mm
(400 micron).
[0218] The ratio of the active ingredients to 10 mg of the carrier
is 6 microg (.mu.g) of FF dihydrate (theoretical delivered dose 4.5
.mu.g), 100 microg (.mu.g) of BDP and 12.5 microg (.mu.g) of
glycopyrronium bromide (theoretical delivered dose 10.0 .mu.g).
[0219] The powder formulations MF and CY were characterized in
terms of the uniformity of distribution of the active ingredients
and aerosol performances after loading it in the multidose dry
powder inhaler described in WO 2004/012801, which is incorporated
herein by reference in its entirety.
[0220] The uniformity of distribution of the active ingredients was
evaluated by withdrawing 12 samples from different parts of the
blend and evaluated by HPLC. The results (mean value.+-.RSD) are
reported in Table 3.
[0221] The evaluation of the aerosol performance was carried out
using the Andersen Cascade Impactor (ACI) according to the
conditions reported in the European Pharmacopeia 6.sup.th Ed 2008,
par 2.9.18, pages 293-295, which is incorporated herein by
reference in its entirety. After aerosolization of 3 doses from the
inhaler device, the ACI apparatus was disassembled and the amounts
of drug deposited in the stages were recovered by washing with a
solvent mixture and then quantified by High-Performance Liquid
Chromatography (HPLC). The following parameters, were calculated:
i) the delivered dose which is the amount of drug delivered from
the device recovered in the all parts of impactor; ii) the fine
particle mass (FPM) which is the amount of delivered dose having a
particle size equal to or lower than 5.0 micron and the extrafine
FPM which is the amount of delivered dose having a particle size
equal to or lower than 2.0 micron; iii) the fine particle fraction
(FPF) which is the percentage of the fine particle dose; and iv)
the MMAD. The results (mean value.+-.S.D) are reported in Table
3.
TABLE-US-00003 TABLE 3 Batch MF Batch CY FF Uniformity of
distribution 100.0 (.+-.3.4) 97.9 (.+-.1.6) Delivered Dose [.mu.g]
5.3 (.+-.0.1) 5.2 (.+-.0.4) Fine Particle Mass < 5 .mu.m [.mu.g]
4.3 4.0 Fine Particle Fraction < 5 .mu.m [%] 75.0 75.9 Extrafine
Particle Mass < 2 .mu.m [.mu.g] 3.2 3.0 Extrafine Particle
Fraction < 2 .mu.m [%] 60.4 57.7 MMAD [.mu.m] 1.2 1.2 GB
Uniformity of distribution 100.0 (.+-.3.6) 101.6 (.+-.2.3)
Delivered Dose [.mu.g] 10.8 (.+-.0.5) 10.5 (.+-.0.6) Fine Particle
Mass < 5 .mu.m [.mu.g] 6.4 6.6 Fine Particle Fraction < 5
.mu.m [%] 53.8 57.2 Extrafine Particle Mass < 2 .mu.m [.mu.g]
4.0 4.0 Extrafine Particle Fraction < 2 .mu.m [%] 37.0 38.1 MMAD
[.mu.m] 1.8 1.8 BDP Uniformity of distribution 99.9 (.+-.3.2) 99.8
(.+-.1.5) Delivered Dose [.mu.g] 84.1 (.+-.3.1) 83.8 (.+-.5.6) Fine
Particle Mass [.mu.g] 66.9 64.5 Fine Particle Fraction [%] 69.9
71.2 Extrafine Particle Mass < 2 .mu.m [.mu.g] 50.0 48.8
Extrafine Particle Fraction < 2 .mu.m [%] 59.5 58.2 MMAD [.mu.m]
1.1 1.1
[0222] From the data in Table 3, it can be appreciated that the
prepared formulations show an excellent homogeneity, an acceptable
delivered dose, and a high respirable fraction (FPF), for all the
three active ingredients.
[0223] They also give rise to a high fraction of particles having a
diameter equal or less than 2 microns (at least more than 35% for
all the active ingredients), indicating that could be suitable for
the prevention and/or treatment of the diseases affecting the
distal tract of the respiratory tree.
[0224] Where a numerical limit or range is stated herein, the
endpoints are included. Also, all values and subranges within a
numerical limit or range are specifically included as if explicitly
written out.
[0225] As used herein the words "a" and "an" and the like carry the
meaning of "one or more."
[0226] Obviously, numerous modifications and variations of the
present invention are possible in light of the above teachings. It
is therefore to be understood that, within the scope of the
appended claims, the invention may be practiced otherwise than as
specifically described herein.
[0227] All patents and other references mentioned above are
incorporated in full herein by this reference, the same as if set
forth at length.
* * * * *